Abstract: FR-OR069

Erythropoietin Is Associated with Total FGF23 Levels in Mice and Humans with CKD

Session Information

Category: Mineral Disease

  • 1202 Mineral Disease: Vitamin D, PTH, FGF-23

Authors

  • Hanudel, Mark R., Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Rappaport, Maxime, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Gabayan, Victoria Rivka, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Ganz, Tomas, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Nemeth, Elizabeta, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
  • Salusky, Isidro B., Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States
Background

We have previously demonstrated that exogenous erythropoietin (EPO) acutely increases bone and circulating FGF23 levels in mice and humans with normal kidney function. It is unknown if EPO has similar effects on FGF23 in the setting of CKD.

Methods

We administered a single dose of EPO to wild type mice with adenine diet-induced CKD. We evaluated associations between serum EPO levels and circulating FGF23 in adult and pediatric non-dialysis CKD patients, and between recombinant human EPO (rhEPO) doses and circulating FGF23 in adult and pediatric dialysis patients.

Results

At six hours post-injection, compared to CKD mice injected with saline, CKD mice intraperitoneally injected with 70 U/g rhEPO demonstrated a 10-fold increase in bone Fgf23 mRNA expression and a 5-fold increase in plasma C-terminal (total) FGF23 (cFGF23) levels, but only a 3-fold increase in plasma intact FGF23 (iFGF23) levels, with a 40% decrease in percentage iFGF23 (iFGF23/total FGF23 x 100%). These data suggest that EPO-induced increases in Fgf23 mRNA expression are coupled with increased FGF23 proteolytic cleavage.

In 70 adult and pediatric non-dialysis CKD patients, after adjustment for eGFR (p<0.001) and phosphate (p<0.001), serum EPO levels positively associated with Log cFGF23 (std. coeff. 0.25, p=0.010; model adjusted R2=0.44). The association remained significant (p=0.023; model adjusted R2=0.42) after further adjustment for age, calcium, Log PTH, TSAT, Log ferritin, Hgb, and Log CRP, none of which were independently associated with Log cFGF23. Unlike cFGF23, Log iFGF23 was not significantly associated with EPO levels.

In 79 adult and pediatric dialysis patients, after adjustment for age (p<0.001), phosphate (p<0.001), calcium (p=0.013), Log CRP (p=0.015), and Log ferritin (p=0.018), Log rhEPO dose positively associated with Log cFGF23 (std. coeff. 0.23, p=0.013; model adjusted R2=0.44). The association remained significant (p=0.016; model adjusted R2=0.43) after further adjustment for Log PTH, TSAT, and Hgb, none of which were independently associated with Log cFGF23. Similar to the non-dialysis CKD patients, Log rhEPO dose was not significantly associated with Log iFGF23.

Conclusion

In CKD patients, erythropoietin has stronger associations with total FGF23 than intact FGF23, suggesting coupling of increased production with increased cleavage.

Funding

  • NIDDK Support